Leptospirosis Workup_ Approach Considerations, Culture, Microscopic Agglutination Testing

10/28/2015 Leptospirosis Workup: Approach Considerations, Culture, Microscopic Agglutination Testing

http://emedicine.medscape.com/article/220563workup 1/7

Leptospirosis WorkupAuthor: Sandra G Gompf, MD, FACP, FIDSA; Chief Editor: Michael Stuart Bronze, MD more...

Updated: Apr 14, 2015

Approach ConsiderationsLeptospires grow slowly in culture, and recovery rates are low. Serologic tests areavailable only in specialized laboratories, and the sensitivity of acute serologic testsis low. Consequently, those tests should not be the basis on which treatment isinitiated. In a patient with compatible symptoms and a plausible exposure history,empiric therapy should be started.

Laboratory studies are used for two purposes: to confirm the diagnosis and todetermine the extent of organ involvement and severity of complications. Laboratoryconfirmation of leptospirosis can be accomplished through isolation of the pathogenor by serologic testing.

Isolation of the leptospires from human tissue or body fluids is the criterionstandard. Consultation with the local microbiology laboratory is essential, becauseprocessing requires specialized techniques. Urine is the most reliable body fluid tostudy because the urine contains leptospires from the onset of clinical symptomsuntil at least the third week of infection.

Other body fluids contain the organism, but the window of opportunity to isolatethem is shorter. Blood and CSF may produce positive cultures during the first 710days of symptoms.

Tissues (ie, liver, muscle, kidney, skin, eyes) are also sources of identification of theleptospires but are obviously more complicated to acquire. Isolation of leptospirescan be difficult and time consuming, involving reference laboratories and oftentaking several months to complete.

More often, paired acute and convalescent serum specimens are used to confirmthe diagnosis. Again, this is a delayed means of confirmation because the acutesera are collected 12 weeks after onset of symptoms, and the convalescent seraare collected 2 weeks afterward.

Antileptospire antibodies in these samples are detected using the microscopicagglutination test (MAT). The Centers for Disease Control and Prevention (CDC)laboratory in Atlanta, Georgia, performs the MAT using 23 leptospire antigens. A 4fold rise in MAT titer between acute and convalescent sera with any of theseantigens confirms the diagnosis of leptospirosis.

Faster laboratory methods may strongly suggest the diagnosis of leptospirosis, butthey may be no more readily available than the CDC laboratory in Atlanta. A singleMAT titer of 1:800 on any sera or identification of spirochetes on darkfieldmicroscopy, when accompanied by the appropriate clinical scenario, is stronglysuggestive.

In suspected leptospirosis, further laboratory studies should be routinely performedto determine the extent and severity of organ involvement after the acute phase ofillness. A complete blood cell count (CBC) is necessary. Findings on generallaboratory studies are as follows:

In patients with mild disease, elevated erythrocyte sedimentation rates andperipheral leukocytosis (3,00026,000 x 109/L) with a left shift are notedSignificant anemia due to pulmonary and gastrointestinal hemorrhage canoccurThe platelet count may be diminished as a component of disseminatedintravascular coagulation (DIC)levels of blood urea nitrogen and serum creatinine may be profoundlyelevated in the anuric or oliguric phaseSerum creatine kinase levels (MM fraction) are often elevated in patientswith muscular involvement.Coagulation times may be prolonged in patients with hepatic dysfunctionand/or DIC On liver function testing, serum bilirubin levels elevate as part ofthe obstructive disease due to capillaritis in the liver. levels of hepatocellulartransaminases are elevated less often and less significantly (usually < 200U/L). Jaundice and bilirubinemia disproportional to hepatocellular damage iscommon in leptospirosis; alkaline phosphatase levels may be elevated 10fold.

On urinalysis, proteinuria may be present. Leukocytes, erythrocytes, hyaline casts,and granular casts may be present in the urinary sediment.

Analysis of the CSF is useful only in excluding other causes of bacterial meningitis.When the CNS becomes involved in leptospirosis, polymorphonuclear leukocytesinitially predominate and are later replaced by monocytes. CSF protein may benormal or elevated, whereas glucose levels remain normal. CSF pressure is normal,but a lumbar puncture can relieve the headache. Leptospires are routinely isolatedfrom the CSF, but this finding does not change management of the disease.

Imaging studies are useful in determining the extent and severity of organinvolvement. This may include chest radiography to evaluate lung disease andbiliary tract ultrasonography in suspected acalculous cholecystitis.

Electrocardiographic (ECG) abnormalities are common during the leptospiremicphase of Weil syndrome. In severe cases, congestive heart failure and cardiogenic



shock may occur.

CultureIsolating the organism by culture allows definitive diagnosis. Leptospires remainviable in anticoagulated blood for as long as 11 days; hence, specimens can bemailed to a reference laboratory for culture. The infecting serovar can be isolatedonly by culture.

Blood cultures may be negative if drawn too early or too late. Leptospires may notbe detected in the blood until 4 days after the onset of symptoms (714 d afterexposure). Once the immune system is activated, blood cultures may again becomenegative. Leptospires may be isolated from the cerebrospinal fluid (CSF) within thefirst 10 days.

Leptospires may be isolated from the urine for several weeks after the initialinfection. In some patients, urine cultures may remain positive for months or yearsafter the onset of illness. Positive urine cultures may take as long as 8 weeks togrow.

Microscopic Agglutination TestingMicroscopic agglutination testing (MAT) uses a battery of antigens taken fromcommon (frequently locally endemic) leptospire serovars. MAT is available only atreference laboratories, such as the Centers for Disease Control and Prevention(CDC).

In a patient with clinical findings consistent with the disease, a single titer exceeding1:200 or serial titers exceeding 1:100 suggest leptospirosis; however, neither isdiagnostic. A 4fold rise in titer between acute and convalescent specimens isconsidered a positive result. The antibody response does not reach detectable levelsuntil the second week of illness, and it can be affected by treatment.

Falsenegative MAT findings may result from testing a single specimen obtainedbefore the immune phase of disease. Test accuracy is also affected by appropriateselection of antigens for the battery, necessitating discussion with the laboratoryabout which serovars are suspected or predominate in the region where the caseoriginated. Falsepositive MAT results may occur with cases of Legionella infection,Lyme disease, and syphilis.

Other TestsScreening tests for leptospirosis, which are easy to perform and provide resultsrelatively rapidly, include the macroscopic slide agglutination test, the Patocslideagglutination test, the microcapsule agglutination test, latex agglutination tests,dipstick tests, and the indirect hemagglutination test. Confirmation of screening testresults (positive or negative) is advisable, however, preferably with MAT.[40]

An immunoglobulin M (IgM) enzymelinked immunoabsorbent assay (ELISA) hasbeen developed. The ELISA uses a broadly reactive antigen and is a standardserologic procedure, as is the MAT.[41] Because it detects IgM, it may be useful fordiagnosis of new infections within 35 days. Positive results should be referred forconfirmatory testing.

Nucleic acid amplification (polymerase chain reaction [PCR])–based techniqueshave been developed to diagnose leptospirosis. PCR can confirm the diagnosisrapidly during the early phase of the disease, when leptospires may be present andbefore antibody titers are detectable, but it requires adequate infrastructure such asappropriate equipment, laboratory space, and skilled personnel. In addition, PCRbased techniques are unable to identify the infecting serovar, which reduce theirepidemiologic and public health value.

Darkfield examination of blood or urine has been used to identify leptospires.However, this technique cannot be recommended, as it frequently leads tomisdiagnosis.

Chest RadiographyThe most common abnormality on chest radiography is bilateral diffuse airspacedisease. Chest radiography may also reveal cardiomegaly and pulmonary edemadue to myocarditis. In patients with alveolar hemorrhage due to pulmonarycapillaritis, the lung parenchyma may contain multiple patchy infiltrates.

Histologic FindingsShortly after inoculation and during the incubation period, leptospires activelyreplicate in the liver. The leptospires then disseminate throughout the body andinfect multiple tissues.

Silver staining and immunofluorescence can identify leptospires in the liver, spleen,kidney, CNS, muscles, and heart. During the acute phase of leptospirosis, histologyreveals these organisms without much inflammatory infiltrate. In addition to thefinding of leptospires during histologic examination, the pathologic effects ofleptospiral toxins are also apparent. See the image below.



Silver stain, liver, fatal human leptospirosis. (This image is in the public domain and thus free ofany copyright restrictions. Courtesy of the Centers for Disease Control/Dr. Martin Hicklin)

Leptospirosis may be seen as an infective systemic vasculitis.[18] Leptospiral toxinsbreak down endothelial cell membranes of capillaries. This toxinmediated processallows for extravasation of blood and leptospires from blood vessels into thesupported parenchyma. Secondarily, because the capillaries are no longerfunctional, ischemia and cell death can occur. Later in infection, mononuclear cellspredominate in the areas of this focal cell necrosis.

Leptospires can be identified in immunologically privileged sites, such as renaltubules, CNS, and the anterior chamber of the eyes, for weeks to months after theinitial infection. In nonhuman animals, the intended hosts of infection, theleptospires establish residence in these immunologically privileged sites. Providedthat the animal survives the initial infection, a chronic carrier state is thenestablished, and histology reveals leptospires at these sites for years after initialinfection.

Treatment & Management

Contributor Information and DisclosuresAuthorSandra G Gompf, MD, FACP, FIDSA Associate Professor of Infectious Diseases and International Medicine,University of South Florida College of Medicine; Chief, Infectious Diseases Section, Director, OccupationalHealth and Infection Control Programs, James A Haley Veterans Hospital

Sandra G Gompf, MD, FACP, FIDSA is a member of the following medical societies: American College ofPhysicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)Judith GreenMcKenzie, MD, MPH, FACP, FACOEM Associate Professor, Director of Clinical Practice,Occupational Medicine Residency Director, University of Pennsylvania School of Medicine

Judith GreenMcKenzie, MD, MPH, FACP, FACOEM is a member of the following medical societies: AmericanCollege of Physicians, American College of Preventive Medicine, National Medical Association, AmericanCollege of Occupational and Environmental Medicine


Ana Paula Velez, MD Assistant Professor of Medicine, Division of Infectious Disease and InternationalMedicine, University of South Florida College of Medicine and James A Haley Veterans Affairs Medical Center;Attending Physician, Moffitt Cancer Center

Ana Paula Velez, MD is a member of the following medical societies: American College of PhysiciansAmericanSociety of Internal Medicine, American Medical Association, Infectious Diseases Society of America


Chief EditorMichael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart GWolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health ScienceCenter; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, AmericanMedical Association, Oklahoma State Medical Association, Southern Society for Clinical Investigation,Association of Professors of Medicine, American College of Physicians, Infectious Diseases Society of America


AcknowledgementsDenise Demers, MD, FAAP Assistant Professor of Pediatrics, Uniformed Services University of the HealthSciences; Attending Physician, Division of Pediatric Infectious Diseases, Department of Pediatrics, Tripler ArmyMedical Center


Juan D Diaz, DO Fellow in Infectious Diseases, University of South Florida College of Medicine, Tampa GeneralHospital, and James A Haley Veterans Hospital


Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics,Division of Infectious Diseases, State University of New York Upstate Medical University

Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha, AmericanAcademy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, PediatricInfectious Diseases Society, and Phi Beta Kappa

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